“Polyketide Antibiotic Biosynthesis:Mechanistic and Structural Basis of the Programming of Multistep Biosynthetic Pathways“
Professor David Cane
Department of Chemistry
The widely used broad spectrum antibiotic erythromycin A is typical of numerous polyketide metabolites produced by Actinomycete bacteria. The structurally and stereochemically complex parent macrolide aglycone, 6-deoxyerythronolide B (6-dEB), is derived from seven units of the simple building block propionic acid. Assembly of propionyl-CoA and its activated derivative, methylmalonyl-CoA, into 6-dEB is catalyzed by a multifunctional megasynthase, deoxyerythronolide B synthase (DEBS), consisting of three large (>350 kD) homodimeric proteins. Each DEBS subunit is organized into groups of catalytic domains known as modules, each of which is responsible for a discrete round of polyketide chain elongation and functional group modification using reactions closely analogous to those of classical saturated fatty acid biosynthesis. The organization, number and composition of the individual DEBS modules are a major determinant of the structure and stereochemistry of the eventually formed macrolide. At the same time, individual domains exercise a varying degree of specificity for their cognate substrates, ranging from strict substrate specificity to relatively broad, but by no means unlimited, permissiveness. We have been particularly interested in using dissected modules to study the molecular basis for the substrate and reaction stereospecificity that characterizes the essential ketoreductase domains .
1.Roselyne Castonguay, Weiguo He, Alice Y. Chen, Chaitan Khosla, and David E. Cane, “Stereospecificity of Ketoreductase Domains of the 6-Deoxyerythronolide B Synthase,” J. Am. Chem. Soc. 129, 13758-13769 (2007).
2.Yinyan Tang, Chu-Young, Kim, Irimpan I. Matthews, Alice Y. Chen, David E. Cane, and Chaitan Khosla, “The 2.7 Å Crystal Structure of a 194-kDa Homodimeric Fragment of the 6-Deoxyerythronolide B Synthase,” Proc. Natl. Acad. Sci. USA, 103, 11124-11129 (2006).
3)Jiaquan Wu, Toby J. Zaleski, Chaitan Khosla, and David E. Cane, “Polyketide Double Bond Biosynthesis. Mechanistic Analysis of the Dehydratase-Containing Module of the Picromycin/Methymycin Polyketide Synthase,” J. Am. Chem. Soc. 127, 17393-17404 (2005).